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We are so fixated on dopamine (DA) and alpa-syn we overlook some important things. Dopamine loss as cause of PD is still only a theory that leaves out norepinephrine (NE). We lose both in PD. When we research Alpha-syn it stands to reason that it must also have the same impact on our forgotten neurotransmitter, right? If you want to say that loss of NE is consequence to loss of DA, that is unlikely as researchers think that NE neurons are hit first.

It is theorized that PD begins in gut, olfactory bulb hit next. then the brain stem. I will stop here for a minute. There are holes in this. First not all of us have gastrointestinal stasis or loss of smell. Next, Alpha-syn is thought to help neurotransmission so it is throughout our system. If they mean Alpha-synuclein clumps are found in the intestine, well that too tells us little. Those clumps, are damaging again only in theory, they are found in normal brains with the person showing no evidence of PD.

Reality is dopamine loss as cause of PD is still just a 50 year old hypothesis. There is actually recent autopsy results showing that we lose more norepinehrine cells than dopamine!?! What if we are treating the primary cause of our disorder inadvertently by treating dopamine and were not even aware of it? Dopamine and Norepinephrine are formed from the common amino acid L-Tyrosine and L-Dopa synthesis - it forms dopamine first then is turned into norepinephrine, so ldopa treats loss of both; how could we know?

Further there is accumulating evidence that our motor symptoms are related to loss of norepephrine, not dopamine. Again you might say wait, we respond to it, but really in essence we are treating both. Research models of PD can help us by isolating the two; looking like NE is responsible. In the MPTP model of PD, they can invoke cell loss of dopamine; lots of it like 80% - two key differences: the animals recover and they do not have motor symptoms. Upset their supply of NE, and they look Parkinsonian and do not compensate for the cell loss. This occurs independent of dopamine loss.

Think of how vulnerable we are to stress. Well, norepinephirine connects directly to adrenals and hypothalamus to manage our stress response. Its home is the locus coeruleus in the brain stem. It regulates our fight or flight response, factors into blood pressure and heart rate, it increases oxygen flow to muscles and brain, sends signals to our spinal chord, and initiates glucose release to our cells. In other words, it makes dopamine look more like a sidekick. Norepinephrine in fact has its own system and here is a list of what it communicates with:

Noradrenergic neurons in the brain form a neurotransmitter system, that, when activated, exerts effects on large areas of the brain. The effects are alertness and arousal, and influences on the reward system.
The noradrenergic neurons originate both in the locus coeruleus and the lateral tegmental field. The axons of the neurons in the locus coeruleus act on adrenergic receptors in:
Amygdala, Cingulate gyrus
Cingulum, Hippocampus
Hypothalamus, Neocortex
Spinal cord, Striatum
Thalamus, Some Brainstem nuclei
Cerebellum

We might never know otherwise in supplying ldopa we are restoring lost NE as well. This might explain why people turn out not to have a loss of dopamine in a brain scan yet look Parkinsonian and respond to Sinemet. It also explains how in autopsies, there are brains with lots of alpha-syn clumps but person never expressed any PD symptoms.

It also explains why a reading cerebro-spinal fluid for checking brain dopamine levels are all over the place with us. Animal models also support this. In

Animal models of PD now also implicate NE in dyskinesisa,

It is looking to me like we have been researching and treating the wrong neurotransmitter?!?! for over 50 years. Think this is crazy? It is entirely possible given that AD researchers thought for sure that misfolding protein was the be and end all. A recent trial on a treatment to disrupt that protein was an epic fail. I hate to see dogmatic thinking lead us down one narrow path.

I think we would find more answers as to why the two areas of our brain that produce neuromelanin are so sensitive and easily disrupted. The locus coeruleus and substantia nigra are both packed rich with neuromelanin. Why are both hit in PD? I hope that finding alpha-syn in our intestines shed some light on that. We are 50 years behind when it comes to NE which has been essentially ignored.

On a positive note there are antidepressents and dugs that work on NE receptors (noradrenergic antagonists) already approved by FDA for other conditions that may better treat us than ldopa alone.

We are so fixated on dopamine (DA) and alpa-syn we overlook some important things. Dopamine loss as cause of PD is still only a theory that leaves out norepinephrine (NE). We lose both in PD. When we research Alpha-syn it stands to reason that it must also have the same impact on our forgotten neurotransmitter, right? If you want to say that loss of NE is consequence to loss of DA, that is unlikely as researchers think that NE neurons are hit first.

It is theorized that PD begins in gut, olfactory bulb hit next. then the brain stem. I will stop here for a minute. There are holes in this. First not all of us have gastrointestinal stasis or loss of smell. Next, Alpha-syn is thought to help neurotransmission so it is throughout our system. If they mean Alpha-synuclein clumps are found in the intestine, well that too tells us little. Those clumps, are damaging again only in theory, they are found in normal brains with the person showing no evidence of PD.

Reality is dopamine loss as cause of PD is still just a 50 year old hypothesis. There is actually recent autopsy results showing that we lose more norepinehrine cells than dopamine!?! What if we are treating the primary cause of our disorder inadvertently by treating dopamine and were not even aware of it? Dopamine and Norepinephrine are formed from the common amino acid L-Tyrosine and L-Dopa synthesis - it forms dopamine first then is turned into norepinephrine, so ldopa treats loss of both; how could we know?

Further there is accumulating evidence that our motor symptoms are related to loss of norepephrine, not dopamine. Again you might say wait, we respond to it, but really in essence we are treating both. Research models of PD can help us by isolating the two; looking like NE is responsible. In the MPTP model of PD, they can invoke cell loss of dopamine; lots of it like 80% - two key differences: the animals recover and they do not have motor symptoms. Upset their supply of NE, and they look Parkinsonian and do not compensate for the cell loss. This occurs independent of dopamine loss.

Think of how vulnerable we are to stress. Well, norepinephirine connects directly to adrenals and hypothalamus to manage our stress response. Its home is the locus coeruleus in the brain stem. It regulates our fight or flight response, factors into blood pressure and heart rate, it increases oxygen flow to muscles and brain, sends signals to our spinal chord, and initiates glucose release to our cells. In other words, it makes dopamine look more like a sidekick. Norepinephrine in fact has its own system and here is a list of what it communicates with:

Noradrenergic neurons in the brain form a neurotransmitter system, that, when activated, exerts effects on large areas of the brain. The effects are alertness and arousal, and influences on the reward system.
The noradrenergic neurons originate both in the locus coeruleus and the lateral tegmental field. The axons of the neurons in the locus coeruleus act on adrenergic receptors in:
Amygdala, Cingulate gyrus
Cingulum, Hippocampus
Hypothalamus, Neocortex
Spinal cord, Striatum
Thalamus, Some Brainstem nuclei
Cerebellum

We might never know otherwise in supplying ldopa we are restoring lost NE as well. This might explain why people turn out not to have a loss of dopamine in a brain scan yet look Parkinsonian and respond to Sinemet. It also explains how in autopsies, there are brains with lots of alpha-syn clumps but person never expressed any PD symptoms.

It also explains why a reading cerebro-spinal fluid for checking brain dopamine levels are all over the place with us. Animal models also support this. In

Animal models of PD now also implicate NE in dyskinesisa,

It is looking to me like we have been researching and treating the wrong neurotransmitter?!?! for over 50 years. Think this is crazy? It is entirely possible given that AD researchers thought for sure that misfolding protein was the be and end all. A recent trial on a treatment to disrupt that protein was an epic fail. I hate to see dogmatic thinking lead us down one narrow path.

I think we would find more answers as to why the two areas of our brain that produce neuromelanin are so sensitive and easily disrupted. The locus coeruleus and substantia nigra are both packed rich with neuromelanin. Why are both hit in PD? I hope that finding alpha-syn in our intestines shed some light on that. We are 50 years behind when it comes to NE which has been essentially ignored.

On a positive note there are antidepressents and dugs that work on NE receptors (noradrenergic antagonists) already approved by FDA for other conditions that may better treat us than ldopa alone.

This mystery to which conductor alludes never ceases to remind me of a game of Clue. Who (bad gene, physical insult, unremitting stress, etc.) killed Mr. Body (us) with what Weapon (DA knife, NE gun, Alpha syn rope, etc.) in what room (the kitchen of the gut, the ballroom of th substantia nigra, the library of the locus coeruleus, etc.)? Conductor, you are so right--after all these years, we don't even know the weapon that hit us, much less who did it and where. All we know for sure is that we are Mr. Body.

Interesting.
Perhaps some folks here may have some feedback about various antidepressants they may have tried that include the neurotransmitter norepinephrine. I believe those were the tricyclic category of antidepressants. I know that the only medication I have used in that category was imipramine- more than 25 years ago. There are now, more recently, also the SNRI class of antidepressants that affect the reuptake of norepinephrine as well as serotonin. The most recognized meds in that category would be effexor and/or cymbalta.
Remember not to mix with MAOIs.

From Wiki

"Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs used in the treatment of major depression and other mood disorders. They are sometimes also used to treat anxiety disorders, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and for the relief of menopausal symptoms.

SNRIs act upon, and increase, the levels of two neurotransmitters in the brain known to play an important part in mood: serotonin, and norepinephrine. These can be contrasted with the more widely-used selective serotonin reuptake inhibitors (SSRIs) which act upon serotonin alone.

Overview of SNRIs

Venlafaxine (Effexor) – The first and most commonly used SNRI. It was introduced by Wyeth in 1994. The reuptake effects of venlafaxine are dose-dependent. At low doses (<150 mg/day), it acts only on serotonergic transmission. At moderate doses (>150 mg/day), it acts on serotonergic and noradrenergic systems, whereas at high doses (>300 mg/day), it also affects dopaminergic neurotransmission.[1]

Desvenlafaxine (Pristiq)[2] – The active metabolite of venlafaxine. It is believed to work in a similar manner, though some evidence suggests lower response rates compared to venlafaxine and duloxetine. It was introduced by Wyeth in May 2008.

Duloxetine (Cymbalta, Yentreve)[3] – By Eli Lilly and Company, has been approved for the treatment of depression and neuropathic pain in August 2004. Duloxetine is contraindicated in patients with heavy alcohol use or chronic liver disease, as duloxetine can increase the levels of certain liver enzymes that can lead to acute hepatitis or other diseases in certain at risk patients. Currently, the risk of liver damage appears to be only for patients already at risk, unlike the antidepressant nefazodone, which, though rare, can spontaneously cause liver failure in healthy patients. [4] Duloxetine is also approved for Major Depressive Disorder (MDD), Generalized Anxiety Disorder (GAD), chronic musculoskeletal pain, including chronic osteoarthritis pain and chronic low back pain (as of October, 2010), and is one of the only three medicines approved by the FDA for Fibromyalgia [1].

Milnacipran (Dalcipran, Ixel, Savella)[5] – Shown to be significantly effective in the treatment of depression and fibromyalgia. The Food and Drug Administration (FDA) approved milnacipran for treatment of fibromyalgia in the United States of America in January 2009, however it is currently not approved for depression in that country. Milnacipran has been commercially available in Europe and Asia for several years.

Levomilnacipran (F2695) – The levo- isomer of milnacipran. Under development for the treatment of depression in the United States and Canada.

Sibutramine (Meridia, Reductil) – An SNRI, which, instead of being developed for the treatment of depression, was widely marketed as an appetite suppressant for weight loss purposes.

Bicifadine (DOV-220,075) – By DOV Pharmaceutical, potently inhibits the reuptake of serotonin and norepinephrine (and dopamine to a lesser extent), but rather than being developed for the already-crowded antidepressant market, it is being researched as a non-opioid, non-NSAID analgesic.

The disease for which SNRIs are mostly indicated, Major Depressive Disorder, is thought to be mainly caused by decreased levels of serotonin and norepinephrine in the synaptic cleft, causing erratic signaling. Due to the monoamine hypothesis of depression, which asserts that decreased concentrations of monoamine neurotransmitters leads to depression symptoms, the following relations were determined: "Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life."[6] SNRIs work by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in an increase in the extracellular concentrations of serotonin and norepinephrine and, therefore, an increase in neurotransmission. Most SNRIs including venlafaxine, desvenlafaxine, and duloxetine, are several fold more selective for serotonin over norepinephrine, while milnacipran is three times more selective for norepinephrine than serotonin. Elevation of norepinephrine levels is thought to be necessary for an antidepressant to be effective against neuropathic pain, a property shared with the older tricyclic antidepressants (TCAs), but not with the SSRIs.[7]
Main article: Reuptake inhibitor

Recent studies have shown that depression may be linked to increased inflammatory response[8], thus attempts at finding an additional mechanism for SNRIs have been made. Studies have shown that SNRIs as well as SSRIs have significant anti-inflammatory action on microglia[9] in addition to their effect on serotonin and norepinephrine levels. As such, it is possible that an additional mechanism of these drugs exists which acts in combination with the previously understood mechanism. The implication behind these findings suggests use of SNRIs as potential anti-inflammatories following brain injury or any other disease where swelling of the brain is an issue. It should be noted, however, that regardless of the mechanism, the efficacy of these drugs in treating the diseases for which they have been indicated has been proven, both clinically and in practice.
Pharmacodynamics

Most SNRIs function alongside primary metabolites and secondary metabolites in order to inhibit reuptake of serotonin, norepinepherine, and trace amounts of dopamine. For example, venlafaxine works alongside its primary metabolite O-desmethylvenlafaxine to strongly inhibit serotonin and norepinephrine reuptake in the brain while . Recent evidence suggests that dopamine and norepinepherine behave in a cotransportational manner, due to dopamine's inactivation by norepinephrine reuptake in the prefrontal cortex, which largely lacks dopamine transporters. Therefore, SNRIs can increase dopamine neurotransmission in this part of the brain.[10] Furthermore, because SNRIs are extremely selective, they have no measurable effects on unintended systems, such as on monoamine oxidase inhibition.[11] Furthermore, studies have shown that SNRIs as well as SSRIs have significant anti-inflammatory action on microglia[12][13][14][15][16][17]

And then the older tri-cyclic medications

Tricyclic antidepressants (TCAs) are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade.

In recent times, the TCAs have been largely replaced in clinical use in most parts of the world by newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), which typically have more favorable side-effects profiles, though they are still sometimes prescribed for certain indications.

Pharmacology

The majority of the TCAs act primarily as serotonin-norepinephrine reuptake inhibitors (SNRIs) by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), respectively, which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.[16][17] Notably, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs).[16] Both serotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders.[18]

In addition to their reuptake inhibition, many TCAs also have high affinity as antagonists at the 5-HT2[19] (5-HT2A[20] and 5-HT2C[20]), 5-HT6,[21] 5-HT7,[22] α1-adrenergic,[19] and NMDA receptors,[23] and as agonists at the sigma receptors[24] (σ1[24] and σ2[25]), some of which may contribute to their therapeutic efficacy, as well as their side effects.[26] The TCAs also have varying but typically high affinity for antagonising the H1[19] and H2[27][28] histamine receptors, as well as the muscarinic acetylcholine receptors.[19] As a result, they also act as potent antihistamines and anticholinergics. These properties are generally undesirable in antidepressants, however, and likely contribute to their large side effect profiles.[26]

Most, if not all, of the TCAs also potently inhibit sodium channels and L-type calcium channels, and therefore act as sodium channel blockers and calcium channel blockers, respectively.[29][30] The former property is responsible for the high mortality rate upon overdose seen with the TCAs via cardiotoxicity.[31]

Finally, and sorry,
this is so long and scattered- in reading about Imipramine (a tricyclic) there is mention of BDNF.

Mechanism of action

Imipramine, a tertiary amine, affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety, ADHD, enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.

The mechanisms of Imipramine's medicinal action include, but are not limited to, effects on:

Serotonin (5-HT): Moderate to strong reuptake inhibition. Imipramine's serotonin reuptake inhibition is almost comparable but still less than its reuptake inhibition of norepinephrine. When compared to other tricyclic antidepressants (with the exception of clomipramine)iImipramine's strong serotonin reuptake inhibition make it more akin to the SSRI class of antidepressants than its metabolite desipramine, which has almost purely noradrenergic effects.

Norepinephrine (NE): Strong reuptake inhibition.

Dopamine (DA): Reuptake and release at D1 and D2 receptors. Similar but less potent than psychostimulants, dopamine agonists, and the atypical antidepressant bupropion on dopaminergic mechanisms (increase in release and blockade of reuptake inhibition). While this effect is much less than the primary effects on NE, SER and ACh, it is nonetheless significant and is partially responsible for the therapeutic benefits of treatment with Imipramine. Enhancement of brain dopamine activity has been implicated in Imipramine's ability to stimulate motor activity and prolong time spent in escape in mice. Regarding dopamine uptake, imipramine is far less potent than most other antidepressants (for example, it has only 5% of the potency of amitryptiline or paroxetine, see the table below).[citation needed]

Acetylcholine (ACh): Imipramine is an anticholinergic. Thus, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the "dementing" effects of anticholinergics increases the potential of Imipramine to cause hallucinations, confusion and delirium in this population. Imipramine is an antagonist at M2 muscarinic acetylcholine receptors (see external links). The blockade of cholinergic (muscarine) receptors is known to cause euphoria, potentially contributing to the mood lifting effects of Imipramine as well. Antimuscarinic effect is also responsible for rapid heart rate (tachycardia).

Epinephrine: Imipramine antagonizes adreno-receptors (II), thus sometimes causing increased heart rate (contributed to by other effects as well), orthostatic hypotension, and a general decrease in the responsiveness of the central nervous system (hence, a contribution to its potent anti-anxiety properties).

σ receptor and Enkephalinase: Activity on σ-receptors is present, but it is very low (Ki of 520 nM on σ-receptors, see references) and it is about half the power of amitryptiline (300 nM).

Histamine: Imipramine is an antagonist at histamine H1 receptors. This contributes to the acute sedative effect that it has in most people. In turn, its anti-histaminergic and general calming effects take place immediately, and, thus, Imipramine is sometimes prescribed as a sleep aid in low doses.

BDNF: BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis. It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours. Chronic Imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promotor, and also reduced expression of hippocampal HDAC5.[5][6]

μ receptor: Imipramine has been shown to increase the expression of μ-opioid receptors in rat forebrain.[7]

I don't think any serious PD research effort is still focused on dopamine alone. As MJFF CEO Todd Sherer says, to paraphrase, the greatest advance in PD research of the last few years is that we know it is not all about dopamine.

__________________
Carey

“Cautious, careful people, always casting about to preserve their reputation and social standing, never can bring about a reform. Those who are really in earnest must be willing to be anything or nothing in the world’s estimation, and publicly and privately, in season and out, avow their sympathy with despised and persecuted ideas and their advocates, and bear the consequences.” — Susan B. Anthony

Conductor, Paula was seriously interested in the effects of neurotransmitters, and you probably have read posts of hers that may contain information relating to this. I know from personal experience that anticholinergics change the neurotransmitter balance enough to give better more fluid movement than dopamine alone. My belief is that there is a delicate balance that is needed, and that if one is affected they all are. Having said that you present a very interesting case, and I am looking forward to hearing more, especially as I am one of that number of people who are dopamine responsive, but have a negative scan. Your theory fits neatly with that, but I still have this idea, that the neurological tightrope is dependent on this fine balance, so that everything harmonizes to produce smooth fluid fast movement. That they are all interdependent. i would love to know whether their have been any animal studies on norepinephrine alone, and how those differ from dopamine alone.

Posting as much to keep this up at the top as anything, and looking forward to more........

Lindy, I know. Paula and I chatted about the dopa trap a few times. Her presence is felt - like a guardian angel for this research. I only mean in sense that is has been so understudied compared to dopamine, yet the scarce research I am finding seems to fill in so many holes. This article I am linking, especially in hands of patients, could be a game changer especially when only other thing doc will say is DBS. We all need to read the following article.

I realize that it is more a balance between neurotransmitters; I didn't mean to imply that DA is now not important. However, maybe dopamine is not responsible for movement deficits? How would know otherwise? How can we go for so long primarily focusing on dopamine loss while NA the neurotransmitter that takes the bigger hit is essentially ignored? Point is the reason things are so "off" whether failed clinical trials or our symptoms and med response is that near everything focuses on DA only when in reality it is a package deal. Like you said interdependent.

This article pretty much sums it all up and does answer your question. In animal models of PD, motor dysfunction occurs either only when NA levels are too low or when animal has DA and NA loss but no motor abnormality in loss of only DA. In the original post I link out to a bibliography that includes more on your question.

The good news is this shows there are more treatment options than we thought. The downside is why have not already been developed?
Noradrenaline in Parkinson Disease. Frontiers in Neuroscience. 2011

In the present review, we analyze the latest evidence for the implication of NA in the pathophysiology of PD obtained from animal models of parkinsonism and from parkinsonian patients. Recent studies have shown that NA depletion alone, or combined with DA depletion, results in motor as well as in non-motor dysfunctions. In addition, by using selective agonists and antagonists of noradrenaline alpha receptors we, and others, have shown that α2 receptors are implicated in the control of motor activity and that α2 receptor antagonists can improve PD motor symptoms as well as L-Dopa-induced dyskinesia. In this review we argue that the loss of NA neurons in PD has an impact on all PD symptoms and that the addition of NAergic agents to dopaminergic medication could be beneficial in the treatment of the disease.

I have theorized for years that mere dopamine replacement is NOT the best therapy for Parkinson's, especially for young onset patients. We probably should be using anything but supplements or agonists for anyone dx prior to age 45-50.

We know that we are going to develop long-term side effects when dx at an early age, but some of the professionals treating the young onset patients must not have received the memo! I often sit in conference presentations or support groups where I have to bite my tongue to keep from blurting out "Where have you been for the last decade?" And that may be a good place to start I.e., make the public aware of such facts.

I must get back to my commitments now, posting here is s another compulsive behavior for which I have a problem!
Peg

I've been taking either Effexor or Cymbalta for the entire duration of my PDDx ; going on 12 y. For what it's worth, I have little problem with dyskinesia. Since both drugs inhibit serotonin and norepinephrine reuptake, my relatively slow progression and mild dysk may be related to that.

I've been taking either Effexor or Cymbalta for the entire duration of my PDDx ; going on 12 y. For what it's worth, I have little problem with dyskinesia. Since both drugs inhibit serotonin and norepinephrine reuptake, my relatively slow progression and mild dysk may be related to that.

Thanks for sharing this! I was on a low dose SSRI for awhile too and biggest benefit is I slept like a normal person 6-8 hours. Was afraid to stay on long term as just one more pill to manage.

You may be right on about it slowing your progression. Recent studies are beginning to show SSRIs may be neuroprotective particularly Celexa and Prozac.

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